Myostatin, or growth/differentiation factor 8 (GDF-8), belongs to the transforming growth factor-β (TGF-β) superfamily (McPherron et al., Nature 387:83-90 (1997)). The human myostatin gene has been cloned (Nestor et al. Proc. Natl. Acad. Sci. 95:14938-43 (1998)). Myostatin is present in human skeletal muscle in both type 1 and type 2 fibers. Myostatin negatively regulates the growth and development of skeletal muscle (Nestor et al., supra).
Myostatin knock-out mice are significantly larger than wild-type mice and have a large and widespread increase in skeletal muscle mass (McPherron et al., Nature 387:83-90 (1997). Two breeds of cattle, characterized by increased muscle mass, have mutations in the myostatin coding sequence (McPherron et al., Proc. Natl. Acad. Sci. 94:12457-61 (1997)). The serum and intramuscular concentrations of immunoreactive myostatin are increased in HIV-infected men with muscle wasting compared with healthy men, and correlate inversely with the fat-free mass index (Nestor et al., supra). Recently, a human child with an apparent loss-of-function mutation in myostatin was identified (Schuelke et al., N Engl J Med. 2004 Jun. 24; 350(26):2682-8). The infant had a marked increase in skeletal muscle mass. Taken together, these data provide genetic and physiological evidence that myostatin is a negative regulator of skeletal muscle growth in humans and contributes to muscle wasting in HIV-infected men.
In view of the above findings, a need exists for a manner of regulating myostatin activity, particularly in individuals who experience muscle wasting as a result of a condition or disease state such as, for example, aging, Autoimmune Deficiency Syndrome (AIDS), Multiple Sclerosis, and cancer. Additionally, GDF-11 is a protein that is closely related to myostatin and participates in neurological functions. Thus, regulators of myostatin are likely to find use in the regulation of GDF-11 and neurological processes as well.
The present invention provides methods and compositions which may be utilized to help individuals with a variety of conditions associated with signaling mediated by TGF-β family members, including myostatin and GDF-11.